The present invention relates generally to a novel class of pyrimidinones that are useful as serine protease inhibitors, and more particularly as Hepatitis C virus NS3 protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
Hepatitis C virus (HCV) is the major cause of transfusion and community-acquired non-A, non-B hepatitis worldwide. Approximately 2% of the world""s population are infected with the virus. In the Unites States, hepatitis C represents approximately 20% of cases of acute hepatitis. Unfortunately, self-limited hepatitis is not the most common course of acute HCV infection. In the majority of patients, symptoms of acute hepatitis resolve, but alanine aminotransferase (a liver enzyme diagnostic for liver damage) levels often remain elevated and HCV RNA persists. Indeed, a propensity to chroninicity is the most distinguishing characteristic of hepatitis C, occurring in at least 85% of patients with acute HCV infection. The factors that lead to chronicity in hepatitis C are not well defined. Chronic HCV infection is associated with increased incidence of liver cirrhosis and liver cancer. No vaccines are available for this virus, and current treatment is restricted to the use of alpha interferon, which is effective in only 15-20% of patients. Recent clinical studies have shown that combination therapy of alpha interferon and ribavirin leads to sustained efficacy in 40% of patients (Poynard et al. Lancet 1998, 352, 1426-1432.). However, a majority of patients still either fail to respond or relapse after completion of therapy. Thus, there is a clear need to develop more effective therapeutics for treatment of HCV-associated hepatitis.
HCV is a positive-stranded RNA virus. Based on comparison of deduced amino acid sequence and the extensive similarity in the 5xe2x80x2 untranslated region, HCV has been classified as a separate genus in the Flaviviridae family, which also includes flaviviruses such as yellow fever virus and animal pestiviruses like bovine viral diarrhea virus and swine fever virus. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.
The RNA genome is about 9.6 Kb in length, and encodes a single polypeptide of about 3000 amino acids. The 5xe2x80x2 untranslated region contains an internal ribosome entry site (IRES), which directs cellular ribosomes to the correct AUG for initiation of translation. As was determined by transient expression of cloned HCV cDNAs, the precursor protein is cotranslationally and posttranslationally processed into at least 10 viral structural and nonstructural (NS) proteins by the action of a host signal peptidase and by two distinct viral proteinase activities. The translated product contains the following proteins: core-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B.
The N-terminal portion of NS3 functions as a proteolytic enzyme that is responsible for the cleavage of sites liberating the nonstructural proteins NS4A, NS4B, NS5A, and NS5B. NS3 has further been shown to be a serine protease. Although the functions of the NS proteins are not completely defined, it is known that NS4A is a protease cofactor and NS5B is an RNA polymerase involved in viral replication. Thus agents that inhibit NS3 proteolytic processing of the viral polyprotein are expected to have antiviral activity.
There are several patents that disclose HCV NS3 protease inhibitors. WO98/17679 describes peptide and peptidomimetic inhibitors with the following formula: Uxe2x80x94E8xe2x80x94E7xe2x80x94E6xe2x80x94E5xe2x80x94E4xe2x80x94NHxe2x80x94CH(CH2G1)xe2x80x94W1, where W is one of a variety of electrophilic groups, including boronic acid or ester. E4 represents either an amino acid or one of a series of peptidomimetic groups, the sythesis of which are not exemplified. HCV protease inhibitors described in the present case are not covered.
Based on the large number of persons currently infected with HCV and the limited treatments available, it is desirable to discover new inhibitors of HCV NS3 protease.
One object of the present invention is to provide compounds, or pharmaceutically acceptable salt forms or prodrugs thereof, which are useful as inhibitors of hepatitis C virus protease, more specifically, the NS3 protease.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt form or prodrug thereof.
It is another object of the present invention to provide a method for the treatment or prevention of HCV comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt form or prodrug thereof.
These and other objects of the invention, which will become apparent during the following detailed description, have been achieved by the discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt forms or prodrugs thereof, wherein R1, R2, R3, R6, R13, W, A1 and A3 are defined below, are effective inhibitors of HCV NS3 protease.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HCV NS3 protease, HCV growth, or both.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of HCV.
[1] Thus, in one embodiment, the present invention provides a compound of Formula (I): 
or a stereoisomer, pharmaceutically acceptable salt form or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CR5R5axe2x80x94, xe2x80x94CH2xe2x80x94CR5R5axe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CR5R5axe2x80x94, xe2x80x94A2xe2x80x94CH2xe2x80x94, xe2x80x94A2xe2x80x94CH2CH2xe2x80x94, or xe2x80x94CH2xe2x80x94A2xe2x80x94CH2xe2x80x94;
A2 is O, S, or NR7;
A3 is H, xe2x80x94C(xe2x95x90O)R9a, xe2x80x94OR9a, xe2x80x94SR9a, xe2x80x94S(xe2x95x90O)R9a, xe2x80x94S(xe2x95x90O)2R9a, xe2x80x94NHCOR9a, xe2x80x94CONHR9a, xe2x80x94NHS(xe2x95x90O)2R9a, xe2x80x94S(xe2x95x90O)2NHR9a, xe2x80x94NHC(xe2x95x90O)OR9a, xe2x80x94OC(xe2x95x90O)NHR9a, xe2x80x94C(xe2x95x90O)OR9a, xe2x80x94Oxe2x80x94C(xe2x95x90O)R9a, xe2x80x94NR8R9a; xe2x80x94NHxe2x80x94A4xe2x80x94R9b; xe2x80x94NHxe2x80x94A4xe2x80x94A5xe2x80x94R9b; or xe2x80x94NHxe2x80x94A4xe2x80x94A5xe2x80x94A6R9b;
W is selected from the group:
xe2x80x94B(OR26)(OR27),
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Oxe2x80x94Q,
xe2x80x94C(xe2x95x90O)CF2C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)Q3,
xe2x80x94C(xe2x95x90O)CF3,
xe2x80x94C(xe2x95x90O)CF2CF3, and
xe2x80x94C(xe2x95x90O)H;
Q is selected from the group:
xe2x80x94(CR10R10c)mxe2x80x94Q1,
xe2x80x94(CR10R10c)mxe2x80x94Q2,
C1-C4 alkyl substituted with Q1,
C2-C4 alkenyl substituted with Q1,
C2-C4 alkynyl substituted with Q1,
an amino acid residue,
xe2x80x94A7xe2x80x94A8, and
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
m is 1, 2, 3, or 4;
Q1 is selected from the group:
xe2x80x94CO2R11, xe2x80x94SO2R11, xe2x80x94SO3R11, xe2x80x94P(O)2R11, xe2x80x94P(O)3R11;
aryl substituted with 0-4 Q1a; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 Q1a;
Q1a is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R19, xe2x80x94C(xe2x95x90O)NR19R19a, xe2x80x94NHC(xe2x95x90O)R19, xe2x80x94SO2R19, xe2x80x94SO2NR19R19a, xe2x80x94NR19R19a, xe2x80x94OR19, xe2x80x94SR19, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
Q2 is xe2x80x94Xxe2x80x94NR12xe2x80x94Z, xe2x80x94NR12xe2x80x94Yxe2x80x94Z, or xe2x80x94Xxe2x80x94NR12xe2x80x94Yxe2x80x94Z;
Q3 is aryl substituted with 0-3 Zc; or
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 Zc;
X is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, or xe2x80x94P(O)3xe2x80x94;
Y is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, or xe2x80x94P(O)3xe2x80x94;
Z is selected from the group:
C1-C4 haloalkyl;
C1-C4 alkyl substituted with 0-3 Za;
C2-C4 alkenyl substituted with 0-3 Za;
C2-C4 alkynyl substituted with 0-3 Za;
C3-C10 cycloalkyl substituted with 0-5 Zb;
aryl substituted with 0-5 Zb;
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zb;
an amino acid residue;
xe2x80x94A7xe2x80x94A8; and
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
Za is selected from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20a, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C3-C10 cycloalkyl substituted with 0-5 Zb;
C3-C10 carbocyle substituted with 0-5 Zb;
aryl substituted with 0-5 Zb; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zb;
Zb is selected from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20a, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C3-C10 cycloalkyl substituted with 0-5 Zc;
C3-C10 carbocyle substituted with 0-5 Zc;
aryl substituted with 0-5 Zc; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zc;
Zc is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20a, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
R1 is selected from the group: H, F;
C1-C6 alkyl substituted with 0-3 R1a;
C2-C6 alkenyl substituted with 0-3 R1a;
C2-C6 alkynyl substituted with 0-3 R1a; and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH, xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, xe2x80x94P(O)2R1b, xe2x80x94P(O)3R1b, xe2x80x94C(xe2x95x90O)NHR1b, xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl);
C1-C4 alkyl substituted with 0-3 R1c;
aryl substituted with 0-5 R1c;
xe2x80x94Oxe2x80x94(CH2)n-aryl substituted with 0-5 R1c;
xe2x80x94Sxe2x80x94(CH2)n-aryl substituted with 0-5 R1c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R1c;
n is 0, 1 or 2;
R1b is H;
C1-C4 alkyl substituted with 0-3 R1c;
C2-C4 alkenyl substituted with 0-3 R1c;
C2-C4 alkynyl substituted with 0-3 R1c;
C3-C6 cycloalkyl substituted with 0-5 R1c;
aryl substituted with 0-5 R1c;
aryl-C1-C4 alkyl substituted with 0-4 R1c; or
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94C(xe2x95x90O)OR1d, xe2x80x94NR1dR1d, xe2x80x94SO2R1d, xe2x80x94SO3R1d, xe2x80x94C(xe2x95x90O)NHR1d, xe2x80x94NHC(xe2x95x90O)R1d, SO2NHR1d, xe2x80x94CF3, xe2x80x94OCF3, C3-C6 cycloalkyl, phenyl, and benzyl;
R1d is selected at each occurrence from the group: H, C1-C4 alkyl, phenyl and benzyl;
R2 is H or C1-C4 alkyl;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHS(xe2x95x90O)2xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94S(xe2x95x90O)2NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0, 1, or 2;
R4 is selected from the group:
C1-C6 alkyl substituted with 0-3 R4a;
C2-C6 alkenyl substituted with 0-3 R4a;
C2-C6 alkynyl substituted with 0-3 R4a;
C3-C10 cycloalkyl substituted with 0-4 R4b;
aryl substituted with 0-5 R4b;
arylxe2x80x94C1-C4 alkyl substituted with 0-5 R4b; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, OC(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4b;
C2-C4 alkenyl substituted with 0-3 R4b;
C2-C4 alkynyl substituted with 0-3 R4b;
C3-C7 cycloalkyl substituted with 0-4 R4c;
aryl substituted with 0-5 R4c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from: H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94OC(xe2x95x90O)NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4c;
C2-C4 alkenyl substituted with 0-3 R4c;
C2-C4 alkynyl substituted with 0-3 R4c;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C1-C4 alkyl substituted with 0-3 R4d;
C2-C4 alkenyl substituted with 0-3 R4d;
C2-C4 alkynyl substituted with 0-3 R4d;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R5 and R5a are, at each occurrence, independently selected from the group: H, C1-C4 alkyl, phenyl and benzyl;
R6 is selected from the group: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, and 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated;
R6a is selected from the group: H, F, Cl, Br, I, xe2x80x94CF3, xe2x80x94NR11R11a, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl;
aryl substituted with 0-3 R6b; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-3 R6b;
R6b is selected from the group: H, F, Cl, Br, I, xe2x80x94CO2R11, NR11R11a, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, C1-C4 alkyl, and C1-C4 haloalkyl;
R7 is H or C1-C4 alkyl;
R8 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, aryl or aryl-C1-C4 alkyl;
R9a is selected from the group: H;
C1-C6 alkyl substituted with 0-3 R9c;
C2-C6 alkenyl substituted with 0-3 R9c;
C2-C6 alkynyl substituted with 0-3 R9c;
C3-C6 cycloalkyl substituted with 0-3 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9b is selected from the group: H, xe2x80x94S(xe2x95x90O)R11, xe2x80x94S(xe2x95x90O)2R11, xe2x80x94S(xe2x95x90O)2NHR11, xe2x80x94C(xe2x95x90O)R11, xe2x80x94C(xe2x95x90O)OR11, xe2x80x94C(xe2x95x90O)NHR11; xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R11;
C1-C6 alkyl substituted with 0-3 R9c;
C2-C6 alkenyl substituted with 0-3 R9c;
C2-C6 alkynyl substituted with 0-3 R9c;
C3-C10 cycloalkyl substituted with 0-4 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
phenyl substituted with 0-5 R9d;
naphthyl substituted with 0-5 R9d;
benzyl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-3 R9e;
C1-C4 alkoxy substituted with 0-3 R9e;
C3-C6 cycloalkyl substituted with 0-3 R9e;
aryl substituted with 0-5 R9e; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 R9e;
R9e is selected at each occurrence from the group:
C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, phenyl, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, and NO2;
R10 is selected from the group: xe2x80x94CO2R11, xe2x80x94NR11R11a, and C1-C6 alkyl substituted with 0-1 R10a;
R10a is selected from the group: halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94CO2R11, NR11R11a, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, and aryl substituted with 0-1 R10b;
R10b is selected from the group: xe2x80x94CO2H, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, and xe2x80x94C(xe2x95x90NH)NH2;
R10c is H or C1-C4 alkyl; alternatively, R10 and R10c can be combined to form a C3-C6 cycloalkyl group substituted with 0-1 R10a;
R11 and R11a are, at each occurrence, independently selected from the group: H;
C1-C6 alkyl substituted with 0-3 R11b;
C2-C6 alkenyl substituted with 0-3 R11b;
C2-C6 alkynyl substituted with 0-3 R11b;
C3-C7 cycloalkyl substituted with 0-3 R11b;
aryl substituted with 0-3 R11b; and
aryl(C1-C4 alkyl)-substituted with 0-3 R11b;
R11b is OH, C1-C4 alkoxy, F, Cl, Br, I, NH2, or xe2x80x94NH(C1-C4 alkyl);
R12 is H or C1-C4 alkyl;
R13 is selected from the group: H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C4 alkyl), aryl and aryl-C1-C4 alkyl;
alternatively, R3 and R13 can be combined to form a 4-7 membered cyclic group consisting of carbon atoms, optionally substituted with C1-C4 alkyl; or R3+R13 is xe2x95x90CR4;
R19 and R19a are independently selected from the group: H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl), C3-C6 cycloalkyl, and C3-C6 cycloalkyl(C1-C4 alkyl);
alternatively, NR19R19a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
R20 and R20a are independently selected from the group: H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl)xe2x80x94, C3-C6 cycloalkyl, and C3-C6 cycloalkyl(C1-C4 alkyl)-;
alternatively, NR20R20a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) xe2x80x94NR28R29,
d) C1-C8 alkoxy, and
when taken together, OR26 and OR27 form:
e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
f) a cyclic boronic amide where said boronic amide contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O; or
g) a cyclic boronic amide-ester where said boronic amide-ester contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
R28 and R29, are independently selected from: H, C1-C4 alkyl, aryl(C1-C4 alkyl)-, and C3-C7 cycloalkyl;
A4, A5, A6, A7, A8, and A9 are independently selected from an amino acid residue; and
an amino acid residue, at each occurence, independently comprises a natural amino acid, a modified amino acid or an unnatural amino acid wherein said natural, modified or unnatural amino acid is of either D or L configuration.
[2] In another embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, or xe2x80x94CH2CH2CH2xe2x80x94;
A3 is H, xe2x80x94C(xe2x95x90O)R9a, xe2x80x94OR9a, xe2x80x94SR9a, xe2x80x94S(xe2x95x90O)R9a, xe2x80x94S(xe2x95x90O)2R9a, xe2x80x94NHCOR9a, xe2x80x94CONHR9a, xe2x80x94NHS(xe2x95x90O)2R9a, xe2x80x94S(xe2x95x90O)2NHR9a, xe2x80x94NHC(xe2x95x90O)OR9a, xe2x80x94OC(xe2x95x90O)NHR9a, xe2x80x94C(xe2x95x90O)OR9a, xe2x80x94Oxe2x80x94C(xe2x95x90O)R9a, xe2x80x94NR8R9a;
xe2x80x94NHxe2x80x94A4xe2x80x94R9b;
xe2x80x94NHxe2x80x94A4xe2x80x94A5xe2x80x94R9b; or
xe2x80x94NHxe2x80x94A4xe2x80x94A5xe2x80x94A6xe2x80x94R9b;
W is selected from the group:
xe2x80x94B(OR26)(OR27),
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Oxe2x80x94Q,
xe2x80x94C(xe2x95x90O)CF2C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)Q3,
xe2x80x94C(xe2x95x90O)CF3,
xe2x80x94C(xe2x95x90O)CF2CF3, and
xe2x80x94C(xe2x95x90O)H;
Q is selected from the group:
xe2x80x94(CR10R10c)mQ1,
xe2x80x94(CR10R10c)mxe2x80x94Q2,
C1-C4 alkyl substituted with Q1,
C2-C4 alkenyl substituted with Q1,
C2-C4 alkynyl substituted with Q1,
an amino acid residue,
xe2x80x94A7xe2x80x94A8, and
xe2x80x94A7xe2x80x94A8xe2x80x94A9;
m is 1, 2, or 3;
Q1 is selected from the group:
xe2x80x94CO2R11, xe2x80x94SO2R11, xe2x80x94SO3R11, xe2x80x94P(O)2R11, xe2x80x94P(O)3R11; aryl substituted with 0-4 Q1a; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 Q1a;
Q1a is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R19, xe2x80x94C(xe2x95x90O)NR19R19a, xe2x80x94NHC(xe2x95x90O)R19, xe2x80x94SO2R19, xe2x80x94SO2NR19R19a, xe2x80x94NR19R19a, xe2x80x94OR19, xe2x80x94SR19, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
Q2 is xe2x80x94Xxe2x80x94NR12xe2x80x94Z, xe2x80x94NR12xe2x80x94Yxe2x80x94Z, or xe2x80x94Xxe2x80x94NR12xe2x80x94Yxe2x80x94Z;
Q3 is aryl substituted with 0-3 Zc; or
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 Zc;
X is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, or xe2x80x94P(O)3xe2x80x94;
Y is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, or xe2x80x94P(O)3xe2x80x94;
Z is selected from the group:
C1-C4 haloalkyl;
C1-C4 alkyl substituted with 0-3 Za;
C2-C4 alkenyl substituted with 0-3 Za;
C2-C4 alkynyl substituted with 0-3 Za;
C3-C10 cycloalkyl substituted with 0-5 Zb;
aryl substituted with 0-5 Zb; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zb;
Za is selected from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20, C(xe2x95x90O)NR20R20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20a, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C3-C10 cycloalkyl substituted with 0-5 Zb;
C3-C10 carbocyle substituted with 0-5 Zb;
aryl substituted with 0-5 Zb; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zb;
Zb is selected from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20a, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C3-C10 cycloalkyl substituted with 0-5 Zc;
C3-C10 carbocyle substituted with 0-5 Zc;
aryl substituted with 0-5 Zc; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zc;
Zc is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20a, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
R1 is selected from the group: H, F;
C1-C6 alkyl substituted with 0-3 R1a;
C2-C6 alkenyl substituted with 0-3 R1a;
C2-C6 alkynyl substituted with 0-3 R1a; and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH, xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, xe2x80x94P(O)2R1b, xe2x80x94P(O)3R1b, xe2x80x94C(xe2x95x90O)NHR1b, xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl);
C1-C4 alkyl substituted with 0-3 R1c;
aryl substituted with 0-5 R1c;
xe2x80x94Oxe2x80x94(CH2)n-aryl substituted with 0-5 R1c;
xe2x80x94Sxe2x80x94(CH2)n-aryl substituted with 0-5 R1c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R1c;
n is 0, 1 or 2;
R1b is H;
Cl-C4 alkyl substituted with 0-3 R1c;
C2-C4 alkenyl substituted with 0-3 R1c;
C2-C4 alkynyl substituted with 0-3 R1c;
C3-C6 cycloalkyl substituted with 0-5 R1c;
aryl substituted with 0-5 R1c;
aryl-C1-C4 alkyl substituted with 0-4 R1c; or
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R1c;
R1c is selected at each occurrence from the group: C1-C4 alkyl, Cl, F, Br, I, OH, SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94C(xe2x95x90O)OR1d, xe2x80x94NR1dR1d, xe2x80x94SO2R1d, xe2x80x94SO3R1d, xe2x80x94C(xe2x95x90O)NHR1d, xe2x80x94NHC(xe2x95x90O)R1d, xe2x80x94SO2NHR1d, xe2x80x94CF3, xe2x80x94OCF3, C3-C6 cycloalkyl, phenyl, and benzyl;
R1d is selected at each occurrence from the group: H, C1-C4 alkyl, phenyl and benzyl;
R2 is H, methyl or ethyl;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHS (xe2x95x90O)2xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94S(xe2x95x90O)2NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0, 1, or 2;
R4 is selected from the group:
C1-C6 alkyl substituted with 0-3 R4a;
C2-C6 alkenyl substituted with 0-3 R4a;
C2-C6 alkynyl substituted with 0-3 R4a;
C3-C10 cycloalkyl substituted with 0-4 R4b;
aryl substituted with 0-5 R4b; aryl-C1-C4 alkyl substituted with 0-5 R4b; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, NR11R11a, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-2 R4b;
C2-C4 alkenyl substituted with 0-2 R4b;
C2-C4 alkynyl substituted with 0-2 R4b;
C3-C7 cycloalkyl substituted with 0-3 R4c;
aryl substituted with 0-5 R4c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94OC(xe2x95x90O)NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4c;
C2-C4 alkenyl substituted with 0-3 R4c;
C2-C4 alkynyl substituted with 0-3 R4c;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O) R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C1-C4 alkyl substituted with 0-3 R4d;
C2-C4 alkenyl substituted with 0-3 R4d;
C2-C4 alkynyl substituted with 0-3 R4d;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from: H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R6 is selected from the group: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, and 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated;
R6a is selected from the group: H, F, Cl, Br, I, xe2x80x94CO2R11, NR11R11a, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl;
aryl substituted with 0-3 R6b; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-3 R6b;
R6b is selected from the group: H, F, Cl, Br, I, xe2x80x94CO2R11, NR11R11a, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, C1-C4 alkyl, and C1-C4 haloalkyl;
R8 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, phenyl or benzyl;
R9a is selected from the group: H;
C1-C6 alkyl substituted with 0-3 R9c;
C2-C6 alkenyl substituted with 0-3 R9c;
C2-C6 alkynyl substituted with 0-3 R9c;
C3-C6 cycloalkyl substituted with 0-3 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9b is selected from the group: H, xe2x80x94S(xe2x95x90O)R11, xe2x80x94S(xe2x95x90O)2R11, xe2x80x94S(xe2x95x90O)2NHR11, xe2x80x94C(xe2x95x90O)R11, xe2x80x94C(xe2x95x90O)OR11, xe2x80x94C(xe2x95x90O)NHR11; xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R11;
C1-C6 alkyl substituted with 0-3 R9c;
C2-C6 alkenyl substituted with 0-3 R9c;
C2-C6 alkynyl substituted with 0-3 R9c;
C3-C10 cycloalkyl substituted with 0-4 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
phenyl substituted with 0-5 R9d;
naphthyl substituted with 0-5 R9d;
benzyl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-3 R9e,
C1-C4 alkoxy substituted with 0-3 R9e,
C3-C6 cycloalkyl substituted with 0-3 R9e,
aryl substituted with 0-5 R9e, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 R9e;
R9e is selected at each occurrence from the group: C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, phenyl, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, and NO2;
R10 is selected from the group: xe2x80x94CO2R11, xe2x80x94NR11R11a, and C1-C6 alkyl substituted with 0-1 R10a;
R10a is selected from the group: halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94CO2R11, NR11R11a, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, and aryl substituted with 0-1 R10b;
R10b is selected from the group: xe2x80x94CO2H, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, and xe2x80x94C(xe2x95x90NH)NH2;
R10c is H or C1-C4 alkyl;
alternatively, R10 and R10c can be combined to form a C3-C6 cycloalkyl group substituted with 0-1 R10a;
R11 and R11a are, at each occurrence, independently selected from the group: H,
C1-C6 alkyl substituted with 0-3 R11b,
C2-C6 alkenyl substituted with 0-3 R11b;
C2-C6 alkynyl substituted with 0-3 R11b;
C3-C7 cycloalkyl substituted with 0-3 R11b;
aryl substituted with 0-3 R11b; and
aryl(C1-C4 alkyl)-substituted with 0-3 R11b;
R11b is OH, C1-C4 alkoxy, F, Cl, Br, I, NH2, or xe2x80x94NH(C1-C4 alkyl);
R12 is H or C1-C4 alkyl;
R13 is selected from the group: H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C4 alkyl), aryl and aryl-C1-C4 alkyl;
alternatively, R3 and R13 can be combined to form a 4-7 membered cyclic group consisting of carbon atoms, optionally substituted with C1-C4 alkyl; or R3+R13 is xe2x95x90CR4;
R19 and R19a are independently selected from the group: H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl), C3-C6 cycloalkyl, and C3-C6 cycloalkyl(C1-C4 alkyl);
alternatively, NR19R19a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
R20 and R20a are independently selected from the group: H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl)-, C3-C6 cycloalkyl, and C3-C6 cycloalkyl(C1-C4 alkyl)-;
alternatively, NR20R20a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) xe2x80x94NR28R29,
d) Cl-C8 alkoxy, and
when taken together, OR26 and OR27 form:
e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
R28 and R29, are independently selected from: H, C1-C4 alkyl, aryl(C1-C4 alkyl)-, and C3-C7 cycloalkyl;
A4, A5, A6, A7, A8, and A9 are independently selected from an amino acid residue; and
an amino acid residue, at each occurence, independently comprises a natural amino acid, a modified amino acid or an unnatural amino acid wherein said natural, modified or unnatural amino acid is of either D or L configuration.
[3] In an alternative embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94;
A3 is H, xe2x80x94C(xe2x95x90O)R9a, xe2x80x94OR9a, xe2x80x94SR9a, xe2x80x94S(xe2x95x90O)R9a, xe2x80x94S(xe2x95x90O)2R9a, xe2x80x94NHCOR9a, xe2x80x94CONHR9a, xe2x80x94NHS(xe2x95x90O)2R9a, xe2x80x94S(xe2x95x90O)2NHR9a, xe2x80x94NHC(xe2x95x90O)OR9a, xe2x80x94OC(xe2x95x90O)NHR9a, xe2x80x94C(xe2x95x90O)OR9a, xe2x80x94Oxe2x80x94C(xe2x95x90O)R9a, xe2x80x94NR8R9a;
xe2x80x94NHxe2x80x94A4xe2x80x94R9b; or
xe2x80x94NHxe2x80x94A4xe2x80x94A5xe2x80x94R9b;
W is xe2x80x94B(OR26)(OR27);
R1 is selected from the group: H;
C1-C4 alkyl substituted with 0-2 R1a;
C2-C4 alkenyl substituted with 0-2 R1a; and
C2-C4 alkynyl substituted with 0-2 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, CF3, CHF2, OH, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl);
C1-C4 alkyl substituted with 0-2 R1c;
aryl substituted with 0-3 R1c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R1c;
R1c is selected at each occurrence from the group: C1-C4 alkyl, Cl, F, Br, I, OH, SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94C(xe2x95x90O)OR1d, xe2x80x94NR1dR1d, xe2x80x94SO2R1d, xe2x80x94SO3R1d, xe2x80x94C(xe2x95x90O)NHR1d, xe2x80x94NHC(xe2x95x90O)R1d, xe2x80x94SO2NHR1d, xe2x80x94CF3, xe2x80x94OCF3, C3-C6 cycloalkyl, phenyl, and benzyl;
R1d is selected at each occurrence from the group: H, C1-C4 alkyl, phenyl and benzyl;
R2 is H;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0, 1, or 2;
R4 is selected from the group:
C1-C4 alkyl substituted with 0-3 R4a;
C2-C4 alkenyl substituted with 0-3 R4a;
C2-C4 alkynyl substituted with 0-3 R4a;
C3-C6 cycloalkyl substituted with 0-2 R4b;
aryl substituted with 0-5 R4b; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a;
C1-C4 alkyl substituted with 0-2 R4b;
C2-C4 alkenyl substituted with 0-2 R4b;
C2-C4 alkynyl substituted with 0-2 R4b;
C3-C7 cycloalkyl substituted with 0-3 R4c;
aryl substituted with 0-5 R4c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, NR11C(xe2x95x90O)OR11a, xe2x80x94OC(xe2x95x90O)NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4c;
C2-C4 alkenyl substituted with 0-3 R4c;
C2-C4 alkynyl substituted with 0-3 R4c;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94CO CF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O) R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C1-C4 alkyl substituted with 0-3 R4d;
C2-C4 alkenyl substituted with 0-3 R4d;
C2-C4 alkynyl substituted with 0-3 R4d;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O) R11, xe2x80x94NR11R11a, xe2x80x94OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R6 is H or C1-C6 alkyl;
R8 is H, methyl, ethyl, propyl, or butyl;
R9a is selected from the group: H;
C1-C4 alkyl substituted with 0-2 R9c;
C2-C4 alkenyl substituted with 0-2 R9c;
C2-C4 alkynyl substituted with 0-2 R9c;
C3-C6 cycloalkyl substituted with 0-2 R9d;
phenyl substituted with 0-3 R9d; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said heterocyclic group is substituted with 0-3 R9d;
R9b is selected from the group: H, xe2x80x94S(xe2x95x90O)R11, xe2x80x94S(xe2x95x90O)2R11, xe2x80x94S(xe2x95x90O)2NHR11, xe2x80x94C(xe2x95x90O)R11, xe2x80x94C(xe2x95x90O)OR11, xe2x80x94C(xe2x95x90O)NHR11; xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R11;
C1-C4 alkyl substituted with 0-2 R9c;
C2-C4 alkenyl substituted with 0-2 R9c;
C2-C4 alkynyl substituted with 0-2 R9c;
C3-C6 cycloalkyl substituted with 0-2 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, phenyl and benzyl;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-1 R9e,
C1-C4 alkoxy substituted with 0-1 R9e,
C3-C6 cycloalkyl substituted with 0-1 R9e,
phenyl substituted with 0-3 R9e, and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-3 R9e;
R9e is selected at each occurrence from the group:
C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, Cl, F, Br, OH, phenyl, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, and NO2;
R11 and R11a are, at each occurrence, independently selected from the group: H,
C1-C4 alkyl substituted with 0-1 R11b,
phenyl substituted with 0-2 R11b; and
benzyl substituted with 0-2 R11b;
R11b is OH, C1-C4 alkoxy, F, Cl, Br, I, NH2, or xe2x80x94NH(C1-C4 alkyl);
R13 is selected from the group: H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C4 alkyl), aryl and aryl-C1-C4 alkyl;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
d) C1-C8 alkoxy, and when taken together, OR26 and OR27 form:
e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 16 carbon atoms;
A4 and A5 are independently selected from an amino acid residue wherein said amino acid residue, at each occurence, is independently selected from the group:
Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, His, Hyp, Ile, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, Val, Abu, Alg, Ape, Cha, Cpa, Cpg, Dfb, Dpa, Gla, Irg, HomoLys, Phe(4-fluoro), Tpa, Asp(OMe), Glu(OMe), Hyp(OMe), Asp(OtBu), Glu(OtBu), Hyp(OtBu), Thr(OtBu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), Pro(OBzl), Thr(OBzl), cyclohexylglycine, cyclohexylalanine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3,3-diphenylalanine.
[4] In another alternative embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94;
A3 is H, xe2x80x94NHCOR9a, xe2x80x94CONHR9a, xe2x80x94NHC(xe2x95x90O)OR9a, xe2x80x94NR8R9a; or xe2x80x94NHxe2x80x94A4xe2x80x94R9b;
W is xe2x80x94B(OR26)(OR27);
R1 is selected from the group: H;
C1-C4 alkyl substituted with 0-2 R1a;
C2-C4 alkenyl substituted with 0-2 R1a; and
C2-C4 alkynyl substituted with 0-2 R1a;
R1a is selected at each occurrence from the group: Cl, F, Br, CF3, and CHF2;
R2 is H;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NNxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0 or 1;
R4 is selected from the group:
C1-C4 alkyl substituted with 0-3 R4a;
C2-C4 alkenyl substituted with 0-3 R4a;
C2-C4 alkynyl substituted with 0-3 R4a;
C3-C6 cycloalkyl substituted with 0-2 R4b;
phenyl substituted with 0-3 R4b;
naphthyl substituted with 0-3 R4b; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a;
C1-C4 alkyl substituted with 0-1 R4b;
C2-C4 alkenyl substituted with 0-1 R4b;
C2-C4 alkynyl substituted with 0-1 R4b;
C3-C7 cycloalkyl substituted with 0-2 R4c;
phenyl substituted with 0-3 R4c;
naphthyl substituted with 0-3 R4c; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94OC(xe2x95x90O)NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-2 R4c;
C2-C4 alkenyl substituted with 0-2 R4c;
C2-C4 alkynyl substituted with 0-2 R4c;
C3-C6 cycloalkyl substituted with 0-3 R4d;
phenyl substituted with 0-3 R4d;
naphthyl substituted with 0-3 R4d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a,
C1-C4 haloalkyl, C1-C4 haloalkoxy;
C1-C4 alkyl substituted with 0-1 R4d;
C2-C4 alkenyl substituted with 0-1 R4d;
C2-C4 alkynyl substituted with 0-1 R4d;
C3-C6 cycloalkyl substituted with 0-2 R4d;
phenyl substituted with 0-3 R4d;
naphthyl substituted with 0-3 R4d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R6 is H, methyl, ethyl, propyl, or butyl;
R8 is H or methyl;
R9ais selected from the group: H;
C1-C4 alkyl substituted with 0-1 R9c;
C2-C4 alkenyl substituted with 0-1 R9c;
C2-C4 alkynyl substituted with 0-1 R9c;
phenyl substituted with 0-3 R9d; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-3 R9d;
R9bis selected from the group: H, xe2x80x94C(xe2x95x90O)R9c, xe2x80x94C(xe2x95x90O)OR9c, xe2x80x94C(xe2x95x90O)NHR9c, C1-C4 alkyl, and phenyl;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, and phenyl;
R9d is selected at each occurrence from the group: CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, and phenyl;
R11 and R11a are, at each occurrence, independently selected from the group: H, methyl, ethyl, propyl, butyl, phenyl and benzyl;
R13 is selected from the group: H, C1-C4 alkyl, phenyl and phenyl-C1-C4 alkyl;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
d) C1-C8 alkoxy, and
when taken together, OR26 and OR27 form:
e) a cyclic boronic ester where said cyclic boronic ester is formed from the group: pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanedio, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol; and
A4 is selected from the group: Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, His, Hyp, Ile, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, Val, Abu, Alg, Ape, Cha, Cpa, Cpg, Dfb, Dpa, Gla, Irg, HomoLys, Phe(4-fluoro), Tpa, Asp(OMe), Glu(OMe), Hyp(OMe), Asp(OtBu), Glu(OtBu), Hyp(OtBu), Thr(OtBu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), Pro(OBzl), Thr(OBzl), cyclohexylglycine, cyclohexylalanine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3,3-diphenylalanine.
[5] In another alternative embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94;
A3 is H, xe2x80x94NHCOR9a, xe2x80x94CONHR9a, xe2x80x94NHC(xe2x95x90O)OR9a, xe2x80x94NR8R9a; or xe2x80x94NHxe2x80x94A4xe2x80x94R9b;
W is pinanediol boronic ester;
R1 is selected from the group: H;
C1-C4 alkyl substituted with 0-2 R1a;
C2-C4 alkenyl substituted with 0-2 R1a; and
C2-C4 alkynyl substituted with 0-2 R1a;
R1a is selected at each occurrence from the group: Cl, F, Br, CF3, and CHF2;
R2 is H;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NNxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0 or 1;
R4 is selected from the group:
C1-C4 alkyl substituted with 0-3 R4a;
C2-C4 alkenyl substituted with 0-3 R4a;
C2-C4 alkynyl substituted with 0-3 R4a;
C3-C6 cycloalkyl substituted with 0-2 R4b;
phenyl substituted with 0-3 R4b;
naphthyl substituted with 0-3 R4b; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a;
C1-C4 alkyl substituted with 0-1 R4b;
C2-C4 alkenyl substituted with 0-1 R4b;
C2-C4 alkynyl substituted with 0-1 R4b;
C3-C7 cycloalkyl substituted with 0-2 R4c;
phenyl substituted with 0-3 R4c;
naphthyl substituted with 0-3 R4c; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94OC(xe2x95x90O)NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-2 R4c;
C2-C4 alkenyl substituted with 0-2 R4c;
C2-C4 alkynyl substituted with 0-2 R4c;
C3-C6 cycloalkyl substituted with 0-3 R4d;
phenyl substituted with 0-3 R4d;
naphthyl substituted with 0-3 R4d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, SO2NR11R11a, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C1-C4 alkyl substituted with 0-1 R4d;
C2-C4 alkenyl substituted with 0-1 R4d;
C2-C4 alkynyl substituted with 0-1 R4d;
C3-C6 cycloalkyl substituted with 0-2 R4d;
phenyl substituted with 0-3 R4d;
naphthyl substituted with 0-3 R4d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R6 is H, methyl, ethyl, propyl, or butyl;
R8 is H or methyl;
R9a is selected from the group: H;
C1-C4 alkyl substituted with 0-1 R9c;
C2-C4 alkenyl substituted with 0-1 R9c;
C2-C4 alkynyl substituted with 0-1 R9c;
phenyl substituted with 0-3 R9d; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-3 R9d;
R9b is selected from the group: H, xe2x80x94C(xe2x95x90O)R9c, xe2x80x94C(xe2x95x90O)OR9c, xe2x80x94C(xe2x95x90O)NHR9c, C1-C4 alkyl, and phenyl;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, and phenyl;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, and phenyl;
R11 and R11a are, at each occurrence, independently selected from the group: H, methyl, ethyl, propyl, butyl, phenyl and benzyl;
R13 is selected from the group: H, C1-C4 alkyl, phenyl and phenyl-C1-C4 alkyl; and
A4 is selected from the group: Val, Ile, Leu, cyclohexylglycine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3,3-diphenylalanine.
[6] In another alternative embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94;
A3 is H, xe2x80x94NHCOR9a, xe2x80x94NHC(xe2x95x90O)OR9a, or xe2x80x94NR8R9a;
W is pinanediol boronic ester;
R1 is H, ethyl, allyl, or 2,2-difluoro-ethyl;
R2 is H;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NNxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0 or 1;
R4 is selected from the group: methyl, isopropyl, t-butyl, phenyl, benzyl, phenethyl, Ph-propyl, phenyl, 2-benzoic acid, 5-isophthalate dimethyl ester, triphenylmethyl, 1-(1-naphthyl)ethyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-ethoxyphenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 4-1-phenyl, 2-CF3-phenyl, 3-CF3-phenyl, 4-F3-phenyl, 4-(trifluoromethoxy)phenyl, 2-(hydroxymethyl)phenyl, 4-(hydroxymethyl)phenyl, 3-cyanophenyl, 3-(acetyl)phenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-(acetyl)phenyl, 2-(methoxycarbonyl)-phenyl, 3-(methoxycarbonyl)-phenyl, 4-(methoxycarbonyl)-phenyl, 2-(ethoxycarbonyl)-phenyl, 3-(ethoxycarbonyl)-phenyl, 4-(ethoxycarbonyl)phenyl, 2-(butoxycarbonyl)phenyl, 2-(tert-butoxycarbonyl)phenyl, 4-(dimethylamino)phenyl, 2-((dimethylamino)carbonyl)phenyl, 2-(methylamino)carbonylphenyl, 2-(aminocarbonyl)phenyl, 2-(methylthio)phenyl, 3-(methylthio)phenyl, 4-(methylthio)phenyl, 2-(methylsulfonyl)phenyl, 3-CF3S-phenyl, 2-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 4-(benzyloxy)phenyl, 2-biphenyl, 4-biphenyl, 2,6-diisopropylphenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-dichlorophenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 5-Cl -2-methoxyphenyl, 4-F-2-nitrophenyl, 3,4,5,-trimethoxyphenyl, 5-Cl-2,4-dimethoxyphenyl, 5-F-2,4-dimethoxyphenyl, Trans-2-phenylcyclopropyl, 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl, 2-quinolinyl, 5-quinolinyl, 1-isoquinolinyl, 2-phenyl-4-quinolinyl, 2-methyl-6-quinolinyl, 2-methyl-4-quinolinyl, 2-3-methylbutyric acid methyl ester, 4-benzyl-1-piperidinyl, 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl, 3-methyl-3-phenyl-piperidinyl, 4-benzyl-4-hydroxy-1-piperidinyl, 4-benzyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1-Benzyloxycarbonyl-piperazinyl, 4-(4-acetylphenyl)-1-piperazinyl, and 3,4-dihydro-2(1H)-isoquinolinyl;
R6 is H;
R8 is H;
R9a is selected from the group: H;
C1-C4 alkyl substituted with 0-1 R9c;
phenyl substituted with 0-3 R9d; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-3 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-2 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, and phenyl;
R9d is selected from the group: CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, and phenyl;
R11 is selected from the group: H, methyl, ethyl, propyl, butyl and benzyl; and
R13 is selected from the group: H, methyl and Ph-propyl.
It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to descibe additional even more preferred embodiments of the present invention.
[7] In another alternative embodiment, the present invention provides a compound, or a stereoisomer or a pharmaceutically acceptable salt form or prodrug thereof, selected from:
benzyl (6S)-6-[{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]amino}carbonyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-ylcarbamate;
benzyl (6S)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl}amino)carbonyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-ylcarbamate;
(6S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide hydrochloride;
(6S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-(benzylamino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-(benzoylamino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-(acetylamino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
benzyl (6S,8RS)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-4-oxo-8-(3-phenylpropyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-ylcarbamate;
benzyl (6S,8S)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-4-oxo-8-(3-phenylpropyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-ylcarbamate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-4-oxo-8-(3-phenylpropyl)-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-4-oxo-8-(3-phenylpropyl)-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-ylpropyl]}-8-amino-8-methyl-4-oxo-8-[(phenylacetyl)amino]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
phenyl (6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-ylcarbamate;
N-((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)-2-phenyl-4-quinolinecarboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(anilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(benzoylamino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-methoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2-fluoroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(3-methoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{[(1-naphthylamino)carbonyl]amino}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(3-cyanoanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(3-acetylanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{[(4-phenoxyanilino)carbonyl]amino}3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-acetylanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{[(2-naphthylamino)carbonyl]amino}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{[((trans-2-phenylcyclopropyl)amino)carbonyl]amino}-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2,4-difluoroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2,5-difluoroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2-methoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{[(2-(trifluoromethyl)anilino)carbonyl]amino}-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(3-fluoroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4, 6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{[(3-(trifluoromethyl)anilino)carbonyl]amino}-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-fluoroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{[(4-(trifluoromethyl)anilino)carbonyl]amino}-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(65,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{[(4-methylanilino)carbonyl]amino}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2,6-diisopropylanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide; methyl 2-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
ethyl 2-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2-isopropylanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-8-{[(3,4,5-trimethoxyanilino)carbonyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{[(3-(methylthio)anilino)carbonyl]amino}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
ethyl 3-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-ethoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{[(4-(methylthio)anilino)carbonyl]amino}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-isopropylanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-ethylanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{[(4-(trifluoromethoxy)anilino)carbonyl]amino}-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-({[(2-phenylethyl)amino]carbonyl}amino)-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
methyl 3-(([((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[([1,1xe2x80x2-biphenyl]-2-ylamino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-8-{[(tritylamino)carbonyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-[({[(1R)-1-(1-naphthyl)ethyl]amino}carbonyl)amino]-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-[({[(1S)-1-(1-phenyl)ethyl]amino}carbonyl)amino]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(isopropylamino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{[(2-phenoxyanilino)carbonyl]amino}-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2,6-difluoroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-[({[(1R)-1-(1-phenyl)ethyl]amino}carbonyl)amino]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-isopropylanilino)carbonyl]amino}-8-methyl-4-oxo-3-([3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-({[4-(dimethylamino)anilino]carbonyl}amino)-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(3,4-dichloroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-tert-butylanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide
methyl 2-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)-3-methylbutanoate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(benzylamino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[({(4-chlorobenzoyl)amino]carbonyl}amino)-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
tert-butyl 2-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
2-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoic acid;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2-chloroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2,5-dimethoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-[(2-toluidinocarbonyl)amino]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(5-chloro-2,4-dimethoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl]-8-{[(2,4-dimethoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2-ethoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(5-chloro-2-methoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
butyl 2-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-({[(2-methylthio)anilino]carbonyl}amino)-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(4-chloroanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{[(4-fluoro-2nitroanilino)carbonyl]amino}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
dimethyl 5-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)isophthalate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-8-[({3-[(trifluoromethyl)sulfanyl]anilino}carbonyl)amino]-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
ethyl 4-({[((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{[(2-nitroanilino)carbonyl]amino}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2-aminoanilino)carbonyl]amino}-8-methyl-4-oxo-3-([3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
N-((6S,8R)-6-[({(1RS)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3,3-difluropropyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)-2-phenyl-4-quinolinecarboxamide;
(6S,8R)-N-{(1RS)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3,3-difluoropropyl}-8-{[(2,5-dimethoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1RS)-1-[(3aS,45,65,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3,3-difluoropropyl}-8-{[(5-chloro-2,4-dimethoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
methyl 2-({[((6S,8R)-6-[({(1RS)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3,3-difluoropropyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-({[2-(methylthionyl)anilino]carbonyl}amino)-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(2-ethoxyanilino)carbonyl]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyllamino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{[(5-chloro-2-methoxyanilino)carbonyl}]amino}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
ethyl 2-({[((6S,8R)-6-[({(1RS)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4, 6-methano-1,3,2-benzodioxaborol-2-yl]-3,3-difluoropropyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)amino]carbonyl}amino)benzoate;
tert-butyl ((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)acetate;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-(2-anilino-2-oxoethyl)-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(4-nitroanilino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-[2-oxo-2-(2-pyridinylamino)ethyl]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(1-naphthylamino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(3-methoxyanilino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-oxo-2-(5-quinolinylamino)ethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7, 8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{2-[(2-methyl-6-quinolinyl)amino]-2-oxoethyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-oxo-2-(3-pyridinylamino)ethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(1-isoquinolinylamino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-2-oxoethyl]-8-methyl-4-oxo-8-[2-oxo-2-(2-quinolinylamino)ethyl]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(2-methoxyanilino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-([1,1xe2x80x2-biphenyl]-4-ylamino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
methyl 4-{[((6S,8S)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-Hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)acetyl]amino}benzoate;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-([benzylamino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{2-[4-(hydroxymethyl)anilino]-2-oxoethyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(4-tert-butylanilino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-2-oxoethyl}-8-methyl-4-oxo-8-{2-[3-(trifluoromethyl)anilino]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{2-[4-(benzyloxy)anilino]-2-oxoethyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
tert-butyl ((6S)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)acetate;
(6S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-(2-anilino-2-oxoethyl)-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8R)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-(3-phenylpropyl)-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-(2-anilino-2-oxoethyl)-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(benzylamino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolol,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(1-isoquinolinylamino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(2-methoxyanilino)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
methyl 2-{[((6S,8S)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)acetyl]amino}benzoate;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-[2-oxo-2-(3-pyridinylamino)ethyl]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{2-[2-(hydroxymethyl)anilino]-2-oxoethyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{2-oxo-2-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-[2-(3-methyl-3-phenyl-1-piperidinyl)-2-oxoethyl]-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(4-benzyl-4-hydroxy-1-piperidinyl)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-[2-oxo-2-(4-phenyl-1-piperazinyl)ethyl]-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide
benzyl 4-[((6S,8S)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl) acetyl]-1-piperazinecarboxylate;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethyl]-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{2-[3-(methylsulfanyl)anilino]-2-oxoethyl}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-{2-[(2-methyl-4-quinolinyl)amino]-2-oxoethyl}-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-[2-(1-naphthylamino)-2-oxoethyl]-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-8-[2-(2-nitroanilino)-2-oxoethyl]-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino)}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-methyl-4-oxo-8-{2-oxo-2-[(2-phenyl-4-quinolinyl)amino]ethyl}-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-(2-{2-[(dimethylamino)carbonyl]anilino}-2-oxoethyl)-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide;
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-(2-{2-[(methylamino)carbonyl]anilino}-2-oxoethyl)-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide; and
(6S,8S)-N-{(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-8-{2-[2-(aminocarbonyl)anilino]-2-oxoethyl}-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide.
This invention also provides compositions comprising one or more of the foregoing compounds and methods of using such compositions in the treatment of hepatitis C virus, such as inhibition of hepatitis C virus protease, in mammals or as reagents used as inhibitors of hepatitis C virus protease in the processing of blood to plasma for diagnostic and other commercial purposes.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a method of treating a viral infection which comprises administering to a host in need of such treatment a therapeutically effective amount of compounds of Formula (I) or pharmaceutically acceptable salt forms or prodrug thereof.
In another embodiment, the present invention provides A method of treating HCV which comprises administering to a host in need of such treatment a therapeutically effective amount of compounds of Formula (I) or pharmaceutically acceptable salt forms or prodrug thereof.
As used throughout the specification, the following abbreviations for amino acid residues or amino acids apply:
Abu is L-aminobutyric acid;
Ala is L-alanine;
Alg is L-2-amino-4-pentenoic acid;
Ape is L-2-aminopentanoic acid;
Arg is L-arginine;
Asn is L-asparagine;
Asp is L-aspartic acid;
Aze is azedine-2-carboxlic acid;
Cha is L-2-amino-3-cyclohexylpropionic acid;
Cpa is L-2-amino-3-cyclopropylpropionic acid
Cpg is L-2-amino-2-cyclopropylacetic acid;
Cys is L-cysteine;
Dfb is L-4,4xe2x80x2-difluoro-1-amino-butyric acid;
Dpa is L-2-amino-3,3-diphenylpropionic acid;
Gla is gamma-carboxyglutamic acid;
Gln is L-glutamine;
Glu is L-glutamic acid;
Gly is glycine;
His is L-histidine;
HomoLys is L-homolysine;
Hyp is L-4-hydroxyproline;
Ile is L-isoleucine;
Irg is isothiouronium analog of L-Arg;
Leu is L-leucine;
Lys is L-lysine;
Met is L-methionine;
Orn is L-ornithine;
Phe is L-phenylalanine;
Phe(4-fluoro) is para-fluorophenylalanine;
Pro is L-proline;
Sar is L-sarcosine;
Ser is L-serine;
Thr is L-threonine;
Tpa is L-2-amino-5,5,5-trifluoropentanoic acid;
Trp is L-tryptophan;
Tyr is L-tyrosine; and
Val is L-valine.
The xe2x80x9cDxe2x80x9d prefix for the foregoing abbreviations indicates the amino acid is in the D-configuration. xe2x80x9cD,Lxe2x80x9d indicates the amino is present in mixture of the D- and the L-configuration. The prefix xe2x80x9cboroxe2x80x9d indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic ester. For example, if R1 is isopropyl and Y1 and y2 are OH, the C-terminal residue is abbreviated xe2x80x9cboroVal-OHxe2x80x9d where xe2x80x9cxe2x80x94OHxe2x80x9d indicates the boronic acid is in the form of the free acid. The pinanediol boronic ester and the pinacol boronic ester are abbreviated xe2x80x9cxe2x80x94C10H16xe2x80x9d and xe2x80x9cxe2x80x94C6H12xe2x80x9d, respectively. Examples of other useful diols for esterification with the boronic acids are 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, and 1,2-dicyclohexylethanediol. Analogs containing sidechain substituents are described by indicating the substituent in parenthesis following the name of the parent residue. For example the analog of borophenylalanine containing a meta cyano group is -boroPhe(mCN)xe2x80x94.
The following abbreviations may also be used herein and are defined as follows. The abbreviation xe2x80x9cDIBALxe2x80x9d means diisobutylaluminum hydride. The abbreviation xe2x80x9cRaNixe2x80x9d means Raney nickel. The abbreviation xe2x80x9cLAHxe2x80x9d means lithium aluminum hydride. The abbreviation xe2x80x9c1,1xe2x80x2-CDIxe2x80x9d means 1,1xe2x80x2-carbonyldiimidazole. The abbreviation xe2x80x9cBnxe2x80x9d means benzyl. The abbreviation xe2x80x9cBOCxe2x80x9d means t-butyl carbamate. The abbreviation xe2x80x9cCBZxe2x80x9d means benzyl carbamate. Other abbreviations are: xe2x80x9cBSAxe2x80x9d, benzene sulfonic acid; xe2x80x9cTHFxe2x80x9d, tetrahydrofuran; xe2x80x9cDMFxe2x80x9d, dimethylformamide; xe2x80x9cEDCIxe2x80x9d, 1-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; xe2x80x9cHOAtxe2x80x9d, 1-hydroxy-7-azabenzotriazole; xe2x80x9cDIEAxe2x80x9d, N,N-diisopropylethylamine; xe2x80x9cBoc-xe2x80x9d, t-butoxycarbonyl-; xe2x80x9cAc-xe2x80x9d, acetyl; xe2x80x9cpNAxe2x80x9d, p-nitro-aniline; xe2x80x9cDMAPxe2x80x9d, 4-N,N-dimethylaminopyridine; xe2x80x9cTrisxe2x80x9d, Tris(hydroxymethyl)aminomethane; xe2x80x9cPyAOPxe2x80x9d, 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate; xe2x80x9cMSxe2x80x9d, mass spectrometry; xe2x80x9cFAB/MSxe2x80x9d, fast atom bombardment mass spectrometry. LRMS(NH3xe2x80x94CI) and HRMS(NH3xe2x80x94CI) are low and high resolution mass spectrometry, respectively, using NH3 as an ion source.
The compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. Also, it is realized that cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The reactions of the synthetic methods claimed herein are carried out in suitable solvents which may be readily selected by one skilled in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then two hydrogens on the atom are replaced.
When any variable (e.g., R4a or R11) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R4a, then said group may optionally be substituted with up to three R4a groups and R4a at each occurrence is selected independently from the definition of R4a. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
xe2x80x9cAmino acid residuexe2x80x9d as used herein, refers to natural, modified or unnatural amino acids of either D- or L-configuration and means an organic compound containing both a basic amino group and an acidic carboxyl group. Natural amino acids residues are Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, His, Hyp, Ile, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, discloses numerous suitable unnatural amino acids and is incorporated herein by reference for that purpose. Additionally, said reference describes, but does not extensively list, acylic N-alkyl and acyclic xcex1,xcex1-disubstituted amino acids. Included in the scope of the present invention are N-alkyl, aryl, and alkylaryl analogs of both in chain and N-terminal amino acid residues. Similarly, alkyl, aryl, and alkylaryl maybe substituted for the alpha hydrogen. Illustrated below are examples of N-alkyl and alpha alkyl amino acid residues, respectively. 
Modified amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, an N-CBZ-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, 3,3-diphenylalanine, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, cyclohexylalanine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, t-butylglycine, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, 2-benzyl-5-aminopentanoic acid.
A list of unnatural amino acids that fall within the scope of this invention is disclosed in a PCT application PCT/US00/18655. The disclosure of which is hereby incorporated by reference.
xe2x80x9cAmino acid residuexe2x80x9d also refers to various amino acids where sidechain functional groups are modified with appropriate protecting groups known to those skilled in the art. xe2x80x9cThe Peptidesxe2x80x9d, Vol 3, 3-88 (1981) discloses numerous suitable protecting groups and is incorporated herein by reference for that purpose. Examples of amino acids where sidechain functional groups are modified with appropriate protecting groups include, but are not limited to, Asp(OMe), Glu(OMe), Hyp(OMe), Asp(OtBu), Glu(OtBu), Hyp(OtBu), Thr(OtBu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), and Thr(OBzl); wherein OMe is methoxy, OtBu is tert-butoxy, and OBzl is benzyloxy.
A preferred list of xe2x80x9camino acid residuexe2x80x9d in the present invention includes, but is not limited to, Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, His, Hyp, Ile, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, Val, Abu, Alg, Ape, Cha, Cpa, Cpg, Dfb, Dpa, Gla, Irg, HomoLys, Phe(4-fluoro), Tpa, Asp(OMe), Glu(OMe), Hyp(OMe), Asp(OtBu), Glu(OtBu), Hyp(OtBu), Thr(OtBu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), Thr(OBzl), cyclohexylglycine, cyclohexylalanine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3,3-diphenylalanine.
A preferred scope of substituent A4 is Val, Ile, Leu, cyclohexylglycine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3,3-diphenylalanine.
As used herein, xe2x80x9calkylxe2x80x9dor xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9ddenotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration having the specified number of carbon atoms and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulpher bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CVFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include xe2x80x9cfluoroalkylxe2x80x9d which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
As used herein, xe2x80x9ccarbocyclexe2x80x9d, xe2x80x9ccarbocyclic ringxe2x80x9d, xe2x80x9ccarbocyclic groupxe2x80x9d, or xe2x80x9ccarbocyclic ring systemxe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclic groupxe2x80x9d, xe2x80x9cheterocyclic ringxe2x80x9d xe2x80x9cheterocyclic ring systemxe2x80x9d or xe2x80x9cHetxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, benzo[1,3]dioxol-yl, 2,3-dihydro-benzo[1,4]dioxin-yl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyrimidopyrimidin-yl, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred 5-10 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, and oxazolidinyl. Also included are fused ring and Spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9cHet-(lower alkyl)-xe2x80x9d as used herein, means a heterocyclic ring as defined above linked through a chain or branched C1-C6 alkyl group.
As used herein, the term xe2x80x9carylxe2x80x9d, or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl and naphthyl.
xe2x80x9cNH2-blocking groupxe2x80x9d as used herein, refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substitutes on these groups maybe either alkyl, aryl, alkylaryl which may contain the heteroatoms, O, S, and N as a substituent or in-chain component. A number of NH2-blocking groups are recognized by those skilled in the art of organic synthesis. By definition, an NH2-blocking group may be removable or may remain permanently bound to the NH2. Examples of suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as, benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl or adamantyloxycarbonyl. Gross and Meinhoffer, eds., The Peptides, Vol 3; 3-88 (1981), Academic Press, New York, and Greene and Wuts Protective Groups in Organic Synthesis, 315-405 (1991), J. Wiley and Sons, Inc., New York disclose numerous suitable amine protecting groups and they are incorporated herein by reference for that purpose. Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methylo xycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolylmethyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; Nxe2x80x2-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; or methanesulfonamide.
As used herein, xe2x80x9ccyclic boronic esterxe2x80x9d is intended to mean a stable cyclic boronic moiety of general formula xe2x80x94B(OR)(OR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or O Cyclic boronic esters are well known in the art. Examples of cyclic boronic ester include, but are not limited to, pinanediol boronic ester, pinacol boronic ester, 1,2-ethanediol boronic ester, 1,3-propanediol boronic ester, 1,2-propanediol boronic ester, 2,3-butanediol boronic ester, 1,2-diisopropylethanediol boronic ester, 5,6-decanediol boronic ester, 1,2-dicyclohexylethanediol boronic ester, diethanolamine boronic ester, and 1,2-diphenyl-1,2-ethanediol boronic ester.
As used herein, xe2x80x9ccyclic boronic amidexe2x80x9d is intended to mean a stable cyclic boronic amide moiety of general formula xe2x80x94B(NR)(NR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or O Examples of cyclic boronic amide include, but are not limited to, 1,3-diaminopropane boronic amide and ethylenediamine boronic amide.
As used herein, xe2x80x9ccyclic boronic amide-esterxe2x80x9d is intended to mean a stable cyclic boronic amide-ester moiety of general formula xe2x80x94B(OR)(NR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or O. Examples of cyclic boronic amide include, but are not limited to, 3-amino-1-propanol boronic amide-ester and ethanolamine boronic amide-ester.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9ctreatingxe2x80x9d refers to: (i) preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
The compounds of this invention are intended to interact with the catalytic serine hydroxyl of Hepatitis C NS3 protease, and therefore incorporate an electrophilic moiety capable of such interaction. In the synthetic schemes below, this moiety, or its synthetic equivalent or precursor, is referred to as a xe2x80x9cserine trapxe2x80x9d and is defined by structure 1.11.
Synthesis of Inhibitors 1.13, 2.3, 2.6, 2.9, 2.12, 2.14
Schemes 1 and 2A-2D illustrate the synthesis of inhibitors of structure 1.13, 2.3, 2.6, 2.9, 2.12, and 2.14. In Schemes 1 and 2A-2D, W is as defined above, P is a nitrogen protecting group, and R is a standard leaving group for carboxylic acids, wherein such protecting and leaving groups are known to one skilled in the art.
The synthesis of inhibitor 1.13 is depicted in Scheme 1. An intermediate in this synthesis, Bicyclic pyrimidinone 1.9 (n=1), is prepared as previously described by Webber et al. (Webber, S. E.; Dragovich, P. S.; Littlefield, E. S.; Marakovits, J. T.; Babine, R. E. WO 99/31122) and is described in the scheme. Lactam 1.1 (n=0-3) is protected as ester 1.2, which is subsequently converted to thiolactam 1.3 by treatment with Lawesson""s reagent. Thiolactam 1.3 is alkylated with MeI to afford 1.4, which is displaced with ammonium chloride providing amidine 1.5. Compound 1.5 is condensed with dimethyl methoxymethylenemalonate to afford bicyclic pyrimidinone 1.6. The methyl ester functionality of ester 1.6 is cleaved with aqueous base to afford acid 1.7, which is then subjected to a Curtius rearrangment using diphenylphosphoryl azide and a suitable alcohol to afford carbamate 1.8. At this point, an R1 substituent may be introduced via NaH induced alkylation of the carbamate nitrogen and the R substituent of the ester may be modified or converted to the corresponding amide via standard (EDCI/HOAt) amide coupling of the corresponding acid. This compound then can be deprotonated with strong base, and the resultant anion reacted with electrophiles. In this way, one or two electrophiles (reaction with R3-Xxe2x80x3 and R13-Xxe2x80x3) may be introduced to give substituted bicyclic pyrimidinone 1.7. In addition, electrophiles such as aldehydes and epoxides may be employed and the resultant carbanols may optionally be eliminated to afford the alkene. At this point, substituents R3 and R13 of compound 1.8 may optionally be modified, followed by deprotection to reveal carboxylic acid 1.9. Peptide coulping of acid 1.10 with serine-trap 1.11 affords amide 1.12. At this point, the R-derived carbamate functionality is cleaved. Optionally, R1, R3, and R13 functionality may be modified and R2 may be introduced to afford inhibitor 1.13.
Inhibitor 2.3 is prepared by deprotonation of lactam 2.1 (n=0-3) and reaction with electrophile(s) to provide compound 2-2, either monosubstituted or disubstituted, followed by a reaction sequence similar to the preparation of inhibitor 1.13. Similarly, inhibitor 2.6 is prepared beginning with cyclic amine 2.4 (N=0-3), which is made according to the chemistry described by Sardina et al. (Blanco et al., J. Org. Chem. 1999, 64, 8786-8793). Cyclic amine 2.4 (n=0-3) is oxidized with ruthenium oxide in a two-phase system (Yoshifuji et al., Chem. Pharma. Bull. 1986, 34, 3873-3878.) to the corresponding lactam 2.5. Lactam 2.5 (n=1) may also be prepared according to chemistry developed by Hruby, V. J. et al. (Soloshonok et al. J. Org. Lett. 2000, 2, 747-750). Following chemistry described above, lactam 2.5 is converted into inhibitor 2.6.
Inhibitor 2.9 is prepared analogously to inhibitor 1.13 from piperazinone 2.8. Compound 2-8 is prepared via reductive amination of piperazinone 2-7, which is prepared according to the chemistry developed by Aebischer et al. (Helv. Chim. Acta 1989, 72, 1043-51). Inhibitor 2.12 is prepared from bicyclic pyrimidinone 2.11 via chemistry analogous to the preparation of inhibitor 1.13. Intermediate 2.11 in turn is prepared via a condensation amidine 1.5 and methylene malonate 2.10 followed by N-bromosuccinimide-promoted unsaturation. Compound 2.11 is prepared following chemistry described by Veale et al. (J. Org. Chem. 1993, 58, 4490-4493.). Inhibitor 2.14 is prepared from morpholinone 2.13 via chemistry analogous to the preparation of inhibitor 1.13. Intermediate 2.13 is prepared via a condensation of CbzSerOtBu and methyl bromoacetate. 
Compounds of the present invention containing peptide segments in A3 can be prepared from commercially available materials by methods known to one skilled in the art of peptide synthesis. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application U.S. Ser. No. 60/242,557, filed Oct. 23, 2000; herein incorporated in its entirety by reference.
Synthesis of a Serine Trap of Structure 1.11
a) Synthesis of xcex1-amino boronic ester
Scheme 3 outlines a route to mono-substituted amino boronic esters. In Scheme 3, a Grignard reagent is reacted with a borate ester 3.12a, which can be prepared by the reaction of pinanediol with trialkylborate, providing boronate 3.12b. Homologation of 3.12b with the anion of dichloromethane gives the xcex1-chloro boronic ester 3.12c. (Matteson, D. S. and Majumdar, D., Organometallics 1983, 2, 1529-1535). Displacement of the chloride by lithium bis(trimethylsilyl)amide gives silyl amine 3.12d, which is converted to the amine hydrochloride salt 3.12e with anhydrous HCl. (Matteson, D. S. and Sadhu, K. M., Organometallics 1984, 3, 1284-1288). Notice that 3.12e is shown protected as the pinanediol ester. This is the preferred protecting group, but other diol protecting groups, for example but not to be limiting the scope of workable and known diol protecting groups, pinacol, 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, are known to those skilled in the art.
Peptide boronic esters can be prepared from commercially available materials by methods known to one skilled in the art of organic synthesis. Peptide boronic acids and esters are generally well known in the art; however, for a general reference to synthesis of peptide boronic esters, see: Kettner, C; Forsyth, T. Houben-Weyl Methods of Organic Chemistry 1999, in press; for a reference to synthesis of fluorinated peptide residues see Matassa et al., PCT Application WO 9964442. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application U.S. Ser. No. 60/142,561, filed Jul. 7, 1999; herein incorporated in its entirety by reference; as well as copending commonly assigned U.S. Provisional Patent Application U.S. Ser. No. 60/145,631, filed Jul. 26, 1999; herein incorporated in its entirety by reference. 
b) Synthesis of xcex1-ketoamide, xcex1-ketoester and xcex1-diketone
xcex1-Ketoamides and other xcex1-keto derivatives are generally introduced in the hydroxy form and oxidized to the active ketone form in the final synthetic step after it is coupled to the pyrazinone carboxylic acid 1.9. Scheme 4 illustrates the synthesis of xcex1-hydroxy esters and xcex1-hydroxy amides. In Scheme 4, substituted acrylate ester 4.13a is aminohydroxylated using a Sharpless""s procedure (Tao, B., Sharpless, K. B. et al. Tetrahedron Lett. 1998, 39, 2507-2510) to Cbz-protected amino alchol 4.13b. Catalytic hydrogenation of 4.13b gives xcex1-hydroxy ketoester 4.13c. Alternatively, 4.13b is hydrolyzed to free acid 4.13d and coupled to amine H2Nxe2x80x94Q to give Cbz-protected amino xcex1-hydroxy amide 4.13e. Catalytic hydrogenation of 4.13e gives xcex1-hydroxy ketoamide 4.13f. For other methods to prepare xcex1-keto esters, amides or other electrophilic carbonyl derivatives, see: Peet et al., Tetrahedron Lett. 1988, 3433-3436; Edwards, P. D. and Bernstein, P. R., Medicinal Res. Reviews 1994, 14, 127-194, and references cited therein; Sharpless et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 451; and Sharpless et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2813. Many of the xcex1,xcex2-unsaturated esters, 4.13a, are commercially available or may be easily prepared from commercially available materials.
Amines of formula H2Nxe2x80x94Q can be prepared from commercially available materials by methods known to one skilled in the art of organic synthesis. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application U.S. Ser. No. 60/168,998, filed Dec. 3, 1999; herein incorporated in its entirety by reference. 
c) Synthesis of Amino Trifluoromethyl and Pentafluoroethyl Ketones
Similar to xcex1-ketoamides and other xcex1-keto derivatives, the trifluoromethyl or pentafluoroethyl ketone functionality is also introduced in the hydroxy form and oxidized to the active ketone form in the final step. Scheme 5 illustrates the synthesis of amino trifluoromethyl alcohol (Skiles et al., J. Med. Chem. 1992, 35, 641-662) and amino pentafluoroethyl alcohol (Ogilvie et al., J. Med. Chem. 1997, 40, 4113-4135). In Scheme 5, a Henry reaction between a nitroalkane R1NO2 and trifluoroacetaldehyde ethyl hemiacetal affords nitro alcohol 5.14a, which is hydrogenated over Raxe2x80x94Ni and the resulting amino alcohol 5.14b is converted to the N-Boc derivative 5.14c. Treatment of the Boc-amine with anhydrous HCl affords the hydrochloride salt 5.14d. A solid-phase synthesis of peptidyl trifluoromethyl ketones is also known, see: Poupart et al., J. Org. Chem. 1999, 64, 1356-1361. Alternatively, condensation of the Weinreb amide 5.15a with CF3CF2Li followed by reduction with NaBH4 gives pentafluoroethyl substituted alcohol 5.15b. Deprotection of 5.15b gives the amino alcohol salt 5.15d. 
d) Synthesis of Difluoro xcex1-ketoamide
Scheme 6 outlines the synthesis of hydroxy difluoro xcex1-ketoamides (see: Veale et al., J. Med. Chem. 1997, 40, 3173-3181; Wolfe et al., J. Med. Chem. 1998, 41, 6-9). In Scheme 6, protected aminoaldehyde 6.16a (For preparation of xcex1-aminoaldehyde, see: Fukuyama et al., J. Am. Chem. Soc. 10 1990, 112, 7050-7051 and Scheidt et al., Bioorg. Med. Chem. 1998, 6, 2477-2499) is reacted with 2-bromo-2,2-difluoroacetate to produce difluoro alcohol 6.16b. The alcohol 6.16b is hydrolyzed to the acid and coupled to an amine H2Nxe2x80x94Q to give 6.16c. The nitrogen protecting group Pg is removed according to procedures known to one skilled in the art (see Greene, T. W. in Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Ed, 1991), producing difluoro xcex1-ketoamide 6.16d. 
The serine traps described above are generally coupled to the free acid of the dihydropyrrolopyrazinone using known peptide coupling procedures, preferably by the phosphonium salt PyAOP (Carpino et al., J. Chem. Soc., Chem. Commun. 1994, 201-203). The alcohol functionality of the hydroxy serine trap is oxidized by procedures known to those skilled in the art, such as Dess-Martin periodinane method (Dess, D. B and Martin, J. C., J. Org. Chem. 1983, 48, 4155-4156) in the final step to give a compound of structure 1.11 and 1.12 wherein W contains an activated carbonyl.
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride (Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy 1995, 2602-2605). A chiral compound may also be directly synthesized using a chiral catalyst or a chiral ligand (Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.